A neonatal Fc receptor (FcRn) has been found as a receptor having a function of transporting an antibody from the fetus to the mother through the placenta. It has recently been suggested that in adults, it contributes to homeostasis of the blood level of an antibody. Both of these functions are caused by pH-dependent binding between IgG and FcRn. This pH dependence is remarkably drastic. Although they bind to each other with a dissociation constant of several nm at pH 6, they hardly bind to each other at pH 7.4. A protein or peptide in the blood has a short half-life because it is brought into an endosome by pinocytosis and is degraded in a lysosome (FIG. 5A). Due to a pH change to acidic in an endosome, an antibody can bind to FcRn that has been expressed in the endosome. The antibody that has bound to FcRn can use an exocytosis pathway so that it is eventually presented extracellularly again, is dissociated from FcRn at a pH returned to 7.4, and returns in the blood (FIG. 5B). Therefore, IgG has a half-life in blood as long as four weeks. IgG having mutation introduced therein to eliminate pH dependence is known to have a decreased half-life in blood. There is also a report on an example of extending a half-life in blood by enhancing its affinity at pH 6 without eliminating pH dependence.
Many of pH-dependent reactions are presumed to occur due to protonation and deprotonation of a histidine (His) residue, because an in vivo pH change is from about 5 to 7.4 and, among 20 amino acids, only the side chain of His has a pKa of 6. In practice, there is a report on an antibody that is prepared by introducing His into the CDR of an antibody and dissociats from an antigen in a pH-dependent manner (for example, Patent Document 1). This antibody binds strongly to an antigen in the blood of pH 7.4 and inhibits the function of the antigen, but when the antibody that binds to the antigen is introduced into an endosome at pH 6.0, it dissociates from the antigen in the endosome and the antibody is recycled, that is, released into the blood again. The document suggests that the antibody can therefore bind to a new antigen in the blood repeatedly.
A His-rich molecule is expected to acquire pH dependence, but preparation of such a molecule limits diversity of the sequence itself and therefore limits the possibility of creating a molecule undergoing pH-dependent binding. In addition, pH dependence attributable only to His is not always sufficient for a change in affinity due to a pH change.